Medical graft device with meshed structure

ABSTRACT

A tissue graft product includes at least one collagen layer comprised of submucosa or renal capsule tissue having slits therein to provide a mesh pattern which in turn establishes a graft structure that is highly deformable. The slits and mesh pattern provide for improved characteristics when utilized as a tissue graft and in particular an external wound care. Preferred devices have multiple submucosa, renal capsule or other collagenous extracellular matrix layers, providing a substantial and lasting scaffold for tissue ingrowth during wound treatment.

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims the benefit of U.S. ProvisionalApplication Ser. No. 60/347,742, which is hereby incorporated byreference in its entirety.

BACKGROUND

The present invention relates generally to medical graft devicescontaining submucosa tissue. In particular, one embodiment of thepresent invention relates to a medical device comprising a collagenlayer including submucosa, wherein the layer has a highly deformable,meshed structure.

As further background, certain extracellular matrix materials, includingsubmucosa tissues, are known tissue graft materials. See, e.g., U.S.Pat. Nos. 4,902,508, 4,956,178, 5,281,422, 5,372,821, 5,554,389,6,099,567, and 6,206,931. As taught in these patents, submucosa tissuesfrom various biological structures such as small intestine, stomach, andthe urinary bladder provide predominantly collagenous layers useful in avariety of surgical procedures where tissue support and/or ingrowth aredesired. As one example, sheet-form submucosa tissue has been suggestedand used as a wound dressing.

Modified tissue graft constructs, including certain perforated formsthereof, are also known. For example, U.S. Pat. Nos. 5,755,791 and5,997,575 teach certain perforated submucosal tissue graft constructs.As taught in these patents, multilaminate submucosal tissue graftconstructs may accumulate tissue fluid in cyst-like pockets betweenadjacent layers after implantation in soft tissue locations. To reducethe occurrence of such pockets, these patents teach that the multi-layersubmucosa graft constructs can be perforated.

Despite prior teaching of certain modified forms of submucosa grafts,needs remain for improved modified forms thereof, having particularutility for example in the treatment of open cutaneous wounds, includingburns. The present invention is addressed to these needs.

SUMMARY OF THE INVENTION

In one preferred embodiment, the invention provides a tissue graftproduct comprised of a meshed layer of collagen including submucosatissue or renal capsule tissue. Advantageous such products include atleast one layer of submucosa having slits therein providing a meshpattern, and wherein the mesh pattern provides to the submucosa or renalcapsule layer an expansion ratio of at least about 1.2:1 when fullyhydrated, preferably at least about 2:1. Desirably, the mesh patternincludes multiple generally parallel rows of slits, wherein the terminiof the slits in adjacent rows are longitudinally offset from oneanother. Preferred mesh patterns will have the adjacent parallel rows ofslits spaced from one another at a distance of about 1 mm to about 10mm, more typically about 3 mm to about 7 mm. Individual slits within themesh pattern can be of equal or differing lengths relative to otherslits, and can have lengths of about 1 mm to about 20 mm, although otherdimensions will also be useful and within the scope of the presentinvention. Most advantageous meshed products of the invention will havean overall collagen layer thickness of at least about 150 microns,usually within the range of about 150 microns to about 1000 microns,which can be provided for example by two or more layers of vertebratesubmucosa tissue or renal capsule tissue bonded together to form asubstantially unitary collagen layer. In other embodiments, theinvention provides medical products that include such a meshed tissuegraft product contained within sterile medical packaging.

Another preferred embodiment of the invention provides a method forgrafting a patient, comprising grafting a patient with a tissue graftproduct as described above. A specific, particularly advantageous methodinvolves the treatment of externally exposed wounds, such as burn woundsto the skin. Highly-exuding skin wounds, including burns and ulcers, canbe treated particularly effectively with meshed submucosal or renalcapsule products having an overall layer thickness of at least about 150microns, in order to provide a lasting scaffold for wound coverage aswell as tissue repair and/or ingrowth. Thus, such wounds are desirablytreated with a meshed product having a collagen layer comprising atleast two bonded submucosa and/or renal capsule layers in accordancewith the invention. Preferred, meshed products of the invention willinclude a plurality of closely-spaced slits or holes sufficient innumber and spacing to allow drainage of the exudate from burn, ulcer orother highly fluidized wounds and prevent the graft from being carriedout of contact with the wounded tissue by such exudate.

Still another preferred embodiment of the invention provides a method ofmanufacturing a tissue graft product, comprising the steps of providinga collagen layer comprised of submucosa or renal capsule tissue, andproducing in said layer a plurality of slits, said slits providing amesh pattern as discussed hereinabove. The meshed product can then besterilized and packaged to provide a medical product.

The present invention provides improvements in tissue grafts, medicalproducts, and methods of their manufacture and use. Additional featuresand objects of the invention will be apparent from the descriptionsherein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a meshed tissue graft device of the invention containingmultiple, bonded submucosa or renal capsule membrane layers.

FIG. 2 provides a cross-sectional view of the meshed tissue graft deviceof FIG. 1 taken along line 2-2 and viewed in the direction of thearrows.

FIG. 3 shows a medical product of the invention including a meshedtissue graft device of FIG. 1 enclosed within a sterile medical package.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

For the purposes of promoting an understanding of the principles of theinvention, reference will now be made to certain embodiments thereof andspecific language will be used to describe the same. It willnevertheless be understood that no limitation of the scope of theinvention is thereby intended, such alterations, further modificationsand further applications of the principles of the invention as describedherein being contemplated as would normally occur to one skilled in theart to which the invention relates.

As disclosed above, the present invention provides a tissue graftproduct that includes a meshed collagen-containing layer comprised ofsubmucosa or renal capsule tissue. The product, in its preferred form,will have multiple slits therein to provide the mesh pattern, and inturn the mesh pattern will provide deformability to thecollagen-containing layer, for example exhibiting an expansion ratio ofat least about 1.2:1 when hydrated. The invention also provides graftingmethods utilizing such tissue graft products, and particularlyadvantageous methods involve the treatment of externally exposed woundssuch as burn wounds to the skin. The invention also provides methods ofmanufacturing such submucosa and/or renal capsule constructs, andmedical articles that include such constructs enclosed within sterilepackaging.

The preferred medical graft products of the invention will includesubmucosa tissue or renal capsule membrane tissue, such as submucosatissue or renal capsule membrane tissue derived from a warm-bloodedvertebrate. Mammalian submucosa or renal capsule membrane tissues arepreferred. In particular, tissues derived from animals raised for meator other product production, e.g. pigs, cattle or sheep, will beadvantageous. Porcine submucosa or renal capsule membrane tissueprovides a particularly preferred starting material for use in thepresent invention.

The submucosa can be derived from any suitable organ or other biologicalstructure, including for example submucosa tissues derived from thealimentary, respiratory, intestinal, urinary or genital tracts of warmblooded vertebrates. Submucosa useful in the present invention can beobtained by harvesting such tissue sources and delaminating thesubmucosa from smooth muscle layers, mucosal layers, and/or other layersoccurring in the tissue source. For additional information as tosubmucosa useful in the present invention, and its isolation andtreatment, reference can be made to U.S. Pat. Nos. 4,902,508, 5,554,389,5,993,844, 6,206,931, and 6,099,567. The renal capsule tissue can alsobe obtained from warm blooded vertebrates, as described moreparticularly in copending U.S. patent application Ser. No. 10/186,150filed Jun. 28, 2002 and copending International patent applicationserial No. PCT/US02/20499 filed Jun. 28, 2002. The submucosa or renalcapsule membrane can retain its original native crosslinking, and/or maybe crosslinked with suitable crosslinking agents as disclosed forexample in U.S. Pat. No. 5,733,337.

As prepared, the submucosa or renal capsule membrane tissue mayoptionally retain growth factors or other bioactive components native tothe source tissue. For example, the submucosa tissue or renal capsuletissue may include one or more growth factors such as basic fibroblastgrowth factor (FGF-2), transforming growth factor beta (TGF-beta),epidermal growth factor (EGF), and/or platelet derived growth factor(PDGF). As well, submucosa or renal capsule membrane tissue used in theinvention may include other biological materials such as heparin,heparin sulfate, hyaluronic acid, fibronectin and the like. Thus,generally speaking, the submucosa or renal capsule membrane tissue mayinclude a bioactive component that induces, directly or indirectly, acellular response such as a change in cell morphology, proliferation,growth, protein or gene expression. Further, in addition or as analternative to the inclusion of such native bioactive components,non-native bioactive components such as those synthetically produced byrecombinant technology or other methods, may be incorporated into thesubmucosa or renal capsule membrane tissue.

Submucosa tissue used in the invention is preferably highly purified,for example, as described in U.S. Pat. No. 6,206,931. Thus, preferredmaterial will exhibit an endotoxin level of less than about 12 endotoxinunits (EU) per gram, more preferably less than about 5 EU per gram, andmost preferably less than about 1 EU per gram. As additionalpreferences, the submucosa material may have a bioburden of less thanabout 1 colony forming units (CFU) per gram, more preferably less thanabout 0.5 CFU per gram. Fungus levels are desirably similarly low, forexample less than about 1 CPU per gram, more preferably less than about0.5 CFU per gram. Nucleic acid levels are preferably less than about 5μg/mg, more preferably less than about 2 μg/mg, and virus levels arepreferably less than about 50 plate forming units (PFU) per gram, morepreferably less than about 5 PFU per gram. These and additionalproperties of submucosa tissue taught in U.S. Pat. No. 6,206,931 may becharacteristic of the submucosa tissue used in the present invention.Preferred renal capsule tissue used in the invention will also have theabove-mentioned characteristics relative to endotoxin, bioburden,fungus, nucleic acid and virus levels.

A typical layer thickness for the as-isolated submucosa layer used inthe invention ranges ranges from about 50 to about 250 microns whenfully hydrated, more typically from about 50 to about 200 microns whenfully hydrated. A typical layer thickness for the as-isolated renalcapsule tissue used in the invention ranges from about 70 to about 100microns, more typically about 80 microns. These layer thicknesses mayvary with the type and age of the animal used as the tissue source. Aswell, these layer thicknesses may vary with the source of the tissueobtained from the animal source.

Submucosa tissue or renal capsule tissue used in the invention may befree of additional, non-native crosslinking, or may contain additionalcrosslinking. Such additional crosslinking may be achieved byphoto-crosslinking techniques, by chemical crosslinkers, or by proteincrosslinking induced by dehydration or other means. Chemicalcrosslinkers that may be used include for example aldehydes such asglutaraldehydes, diimides such as carbodiimides, e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, ribose orother sugars, acyl-azide, sulfo-N-hydroxysuccinamide, or polyepoxidecompounds, including for example polyglycidyl ethers such asethyleneglycol diglycidyl ether, available under the trade name DENACOLEX810 from Nagese Chemical Co., Osaka, Japan, and glycerol polyglycerolether available under the trade name DENACOL EX 313 also from NageseChemical Co. Typically, when used, polyglycerol ethers or otherpolyepoxide compounds will have from 2 to about 10 epoxide groups permolecule.

When additionally crosslinked, submucosa or renal capsule tissues of theinvention can be additionally crosslinked internally within a singlelayer, and/or crosslinking may be used in whole or in part to bondmultiple submucosa layers to one another. Thus, additional crosslinkingmay be added to individual submucosa or renal capsule layers prior tobonding to one another, during bonding to one another, and/or afterbonding to one another.

Meshed medical devices of the invention may include for example a singlesubmucosa or renal capsule tissue layer, or may include a plurality (twoor more) of submucosa or renal capsule tissue layers bonded to oneanother, to provide the overall collagen layer. Preferred devices of theinvention will include multiple submucosa or renal capsule tissue layersbonded to one another so as to provide an overall collagen layerthickness of at least about 150 microns, typically ranging from about150 to about 1000 microns, and in certain embodiments ranging from about200 to about 1000 microns. Such relatively thick layers, when meshed inaccordance with the invention, provide particularly advantageous andlasting collagen scaffolds for tissue ingrowth, especially in the fieldof wound care such as burn and wound care. In addition to suchthicknesses, typical tissue graft products of the invention insheet-form will have lengths and widths ranging from about 2 cm to about50 cm.

In accordance with the invention, the submucosa-containing or renalcapsule-containing collagen layer will preferably be processed so as toexhibit a meshed structure. Such a meshed structure will have aplurality of slits therein to provide a mesh pattern, and the meshpattern will provide deformability to the structure, especiallyexpandability. In this regard, in the preferred constructs, expansion orother deformation of the meshed structure will widen the openingscreated by the slits of the mesh pattern, by lateral and/or verticaldisplacement of the edges of the slits relative to one another.Preferred devices of the invention will have a mesh pattern providing anexpansion ratio of at least about 1.2:1 when the layer is completelyhydrated, more preferably at least about 2:1, and most preferably atleast about 3:1. Such highly deformable structures provide surprisinglybeneficial properties to the graft product, particularly in the field ofwound care.

With reference now to FIG. 1, shown is an illustrative meshed tissuegraft device of the present invention. The graft device 10 includes alayer of collagen 11 comprised of submucosa tissue or renal capsuletissue. Illustratively, layer 11 can be formed from a single submucosaor renal capsule tissue layer, but is preferably formed from a pluralityof submucosa or renal capsule tissue layers. With reference to FIG. 2,shown is a cross sectional view of device 10 taken along line 2-2 andviewed in the direction of the arrows. Shown is layer 11 including afirst submucosa or renal capsule layer 11A bonded to a second submucosaor renal capsule layer 11B to form a substantially unitarycollagen-containing layer 11. In this regard, it is understood that FIG.2 is illustrative but not limiting of the invention, and that thecollagen layer 11 can also be made of more than two submucosa or renalcapsule layers, for example at least three, four, five, six, seven, oreight or more submucosa or renal capsule tissue layers. In this fashion,devices of varying thickness, strengths, and longevity upon implantationcan be produced.

With reference again to FIG. 1, collagen layer 11 includes a meshedpattern formed by a plurality of slits 12 created in layer 11. Inparticular slits 12 are arranged in a plurality of relatively parallelrows R1 through R14. The termini of the slits in a particular row areoffset relative to the termini of the slits in an adjacent row. Inaddition, the termini of slits in an adjacent row occur along the lengthof the slits in an adjacent row when considered in the lateraldirection. Thus, the termini 13A and 13B of a slit in R1 are staggeredrelative to the termini 14A and 14B of a slit in R2, considered in thelongitudinal direction (in which the elongate slits run vertical in FIG.1). On the other hand, considered in a second lateral direction (900 tothe first direction), the termini 14A and 14B of slits in R2 fall withinthe length of the slits in R1—i.e., between termini 13A and 13B andtermini 15A and 15B. Having the slits in this arrangement provides ameshed collagen layer 11 which is substantially deformable or expandablein the horizontal direction of FIG. 1. That is, upon applying an outwardforce to the material to increase the distance between edges 16 and 17of the layer 11, the material deforms so as to expand in the horizontaldirection. As the material expands, the slits 12 of the layer 11 arewidened by lateral and/or vertical movement of the slit edges relativeto one another, thus expanding the openings provided by slits 12. Inparticular, in the mesh pattern shown in FIG. 1, such expansion to asubstantial extent will create generally hexagonal shape openings in themeshed device 10. It has been found that these and other meshedstructures which provide for deformability of the device 10significantly improve the properties of the device 10 for use in tissuegrafting, and for wound care in particular. Importantly, suchdeformability and expandability of the openings defined by slits 12facilitates high level drainage of wounds to which the material isapplied. In addition, the meshed structure provides deformability to theexternal dimensions of device 10 so that upon its application it can beexpanded or deformed to improve the size and/or shape of the materialfor application to the wound.

The meshed structure of the device 10 or other meshed patterns can becreated using suitable meshing devices designed for processing skinautograft sections. Such devices typically include a cylindrical drumcutter with a plurality of edges for providing the slit pattern of themesh. A variety of such devices are known and can be used in theinvention. For additional information as to meshers, reference may bemade to U.S. Pat. Nos. 5,004,468, 6,063,094, 3,472,228, 3,358,688, and3,640,279. These and other devices incorporating a meshing drum providefor a convenient, high-through put method of preparing meshed submucosaor renal capsule devices of the invention. It will be understood,however, that the mesh pattern can be made by hand-cutting the materialor by using appropriate cutting tools with multiple blades to cut theslits to provide the mesh pattern.

With reference now to FIG. 3, shown is a medical product 20 of theinvention including meshed graft device 10 sealed within sterile medicalpackaging. In particular, medical product 20 has packaging including abacking layer 21 and a front film layer 22 (shown partially drawn awayfrom backing layer 21). Graft device 11 is sealed between backing layer21 and film 22 utilizing a boundry of pressure-adhesive 23 as isconventional in medical packaging. A cut-out 24 may be provided in thebacking layer 21 to assist a user in separating the film layer 22 fromthe backing layer 21.

The final, packaged product is provided in a sterile condition. This maybe achieved, for example, by irradiation, ethylene oxide gas, or anyother suitable sterilization technique, and the materials and otherproperties of the medical packaging will be selected accordingly.

Meshed graft devices of the invention can be used in graftingapplications for treatment of human or other animal conditions. In onepreferred application, the meshed materials of the invention are used inthe treatment of wounds and in particular open, cutaneous wounds. Open,cutaneous wounds may be classified into one of four grades depending onthe depth of the wound. A Grade I wound is limited to the epithelium. AGrade II wound extends into the dermis. A Grade III wound extends intothe subcutaneous tissue; and, a Grade IV wound (or full-thickness wound)exposes bone. The term “partial thickness wound” refers to wounds thatencompass Grades I-III; examples of partial thickness wounds includeburn wounds, pressure sores, venous stasis ulcers, and diabetic ulcers.An especially advantageous application of meshed products of theinvention is in the treatment of partial thickness open cutaneouswounds, including burns and ulcers. These wounds are often chronic (e.g.lasting at least about 30 days untreated), and benefit significantlyfrom the application of meshed graft products of the present invention.Burn and ulcer wounds also exude fluids at a high level. Graft productsof the invention will allow passage of the significant exudant, whichfacilitates maintenance of the graft products in contact with thewounded tissue, rather than floating off the wound tissue.

In use, the physician, veterinarian or other user of the devices of theinvention will prepare the wound for treatment in a conventionalfashion, which may for example include cleaning and/or debridement ofthe wound with water, physiologic saline or other solutions, andpotentially also treating the wound with antibiotics or othertherapeutic agents. The meshed device of the invention will be appliedto the wound in a fashion to facilitate and promote healing of thewound. In this regard, the meshed device may be applied in a dehydrated,partially hydrated, or fully hydrated state. Once grafted, the meshedmaterial of the invention will hydrate (if not previously hydrated) andremain generally in place either alone or in combination with otherwound dressing materials applied below or on top of the meshed material.In the treatment of open cutaneous wounds, it has been found thatmeshed, single-submucosa-layer devices are quickly resorbed by the bodyand do not provide a most beneficial, lasting matrix for tissueingrowth. Therefore, wound repair devices of the invention willpreferably include a plurality of submucosa layers bonded to oneanother, to provide a lasting matrix. The layer bond may be achieve, forexample, by one or more of chemical crosslinking as discussed above,dehydrothermal bonding under conditions of freeze drying or vacuumpressing, bonding agents, or other known techniques. The need for athicker, lasting matrix has been found to be particularly acute inchronic burns or ulcers wherein continuous, prolonged wound coverage andhealing are paramount. A similar layer-bonding and meshing technique canbe used with other relatively thin, resorbable extracellular matrixlayers, which also form a part of the present inventive embodiment.

For the purpose of promoting a further understanding of the presentinvention and its features and advantages, the following specificexamples are provided. It will be understood that these examples areillustrative, and not limiting, of the invention.

EXAMPLE 1

A thirty-foot long section of whole intestine from a mature adult hog isrinsed with water. This material is then treated in a 0.2 percent byvolume peracetic acid in a 5 percent by volume aqueous ethanol solutionfor a period of two hours with agitation. The tela submucosa layer isthen delaminated in a disinfected casing machine from the wholeintestine. The delaminated tela submucosa is rinsed four times withsterile water and tested for impurities or contaminants such asendotoxins, microbial organisms, and pyrogens. The resultant tissue wasfound to have essentially zero bioburden level. The tela submucosa layerseparated easily and consistently from the whole intestine and was foundto have minimal tissue debris on its surface.

EXAMPLE 2

A unitary collagen layer containing two dehydrothermally or chemicallybonded submucosa or renal capsule layers is processed as follows. Thelayer, in a dried state, is processed with a skin graft mesher availablefrom Padgett Instruments, set at an expansion ratio of 4:1. Theresulting double-layer, meshed medical device exhibits satisfactoryproperties, and an expansion ratio of at least 2:1 when hydrated. Whenapplied to a wound, such as a burn or ulcer wound, the meshed medicalconstruct of this Example provides a highly drained yet lasting scaffoldand protective layer to promote healing of the wound.

While the invention has been illustrated and described in detail in thedrawings and foregoing description, the same is to be considered asillustrative and not restrictive in character, it being understood thatonly the preferred embodiment has been shown and described and that allchanges and modifications that come within the spirit of the inventionare desired to be protected. In addition, all patents and otherpublications cited herein are indicative of the abilities of thoseordinarily skilled in the art, and each such patent and publication ishereby incorporated herein by reference in its entirety as ifindividually incorporated by reference and fully set forth.

1. A tissue graft product comprising a submucosa-containing or renalcapsule-containing collagen layer, said collagen layer having aplurality of slits therein providing a mesh pattern.
 2. A tissue graftproduct according to claim 1, wherein said collagen layer comprisesintestinal submucosa, stomach submucosa, urinary bladder submucosa, oruterine submucosa.
 3. A tissue graft product according to claim 2,wherein said collagen layer comprises small intestinal submucosa.
 4. Atissue graft product according to claim 1, wherein said collagen layercomprises at least two submucosa layers, said submucosa layers bondedtogether.
 5. The tissue graft product according to claim 4, wherein saidsubmucosa layers are bonded together by a chemical crosslinker.
 6. Thetissue graft product according to claim 4, wherein said collagen layersare bonded together in the absence of a chemical crosslinker.
 7. Thetissue graft product according to claim 6, wherein said collagen layersare bonded together by dehydration bonding.
 8. The tissue graft productaccording to claim 4, wherein said submucosa layers are bonded to form asubstantially unitary collagen layer.
 9. The tissue graft productaccording to claim 8, wherein said collagen layers are bonded oversubstantially the entire area in which they contact one another.
 10. Atissue graft product according to claim 1, wherein said mesh pattern iseffective to provide an expansion ratio of at least about 1.2:1 to saidcollagen layer in a hydrated condition.
 11. A tissue graft productaccording to claim 10, wherein said expansion ratio is at least about2:1.
 12. A tissue graft product according to claim 10, wherein saidexpansion ratio is at least about 3:1.
 13. A tissue graft productaccording to claim 4, wherein said mesh pattern is effective to providean expansion ratio of at least about 1.2:1 to said collagen layer in ahydrated condition.
 14. A tissue graft product according to claim 13,wherein said submucosa layers each have a thickness of about 50 micronsto about 200 microns in a hydrated condition.
 15. A tissue graft productaccording to claim 1, said collagen layer exhibiting a sheet form.
 16. Atissue graft product according to claim 14, said collagen layerexhibiting a sheet form.
 17. A method for treating an open cutaneouswound on a patient, comprising: applying to the wound a tissue graftproduct comprising a submucosa-containing or renal capsule-containingcollagen layer, said submucosa-containing collagen layer having aplurality of slits therein providing a mesh pattern.
 18. A methodaccording to claim 17, wherein said wound is a burn or ulcer.
 19. Amethod according to claim 18, wherein said collagen layer comprises atleast two submucosa layers.
 20. A method according to claim 17, whereinsaid mesh pattern is effective to provide an expansion ratio of at leastabout 1.2:1 to said collagen layer in a hydrated condition.
 21. A methodfor preparing a tissue graft product, comprising: providing asubmucosa-containing or renal capsule-containing collagen layer; andproducing in said collagen layer a plurality of slits, said slitsproviding a mesh pattern
 22. A method according to claim 21, whereinsaid collagen layer includes at least two submucosa layers, saidsubmucosa layers bonded to one another.
 23. A method according to claim22, wherein said submucosa layers are dehydrothermally bonded to oneanother.
 24. A method according to claim 22, wherein said submucosalayers are bonded to one another with a chemical crosslinker.
 25. Amethod according to claim 22, wherein said mesh pattern is effective toprovide an expansion ratio of at least about 1.2:1 to said collagenlayer in a hydrated condition.
 26. A tissue graft construct, comprising:a collagen-containing layer comprising at least two extracellular matrixlayers bonded to one another to provide a multi-layer construct; saidcollagen-containing layer having a plurality of slits providing a meshpattern.
 27. A tissue graft construct according to claim 26, whereinsaid collagen-containing layer comprises at least two submucosa layers,said submucosa layers bonded to one another.
 28. A tissue graft productaccording to claim 27, wherein said submucosa is intestinal submucosa,stomach submucosa, urinary bladder submucosa, or uterine submucosa. 29.A tissue graft product according to claim 28, wherein said submucosa issmall intestinal submucosa.
 30. A tissue graft product according toclaim 26, wherein said mesh pattern is effective to provide an expansionratio of at least about 1.2:1 to said collagen-containing layer in ahydrated condition.
 31. A medical product, comprising: a sterilepackage; and a tissue graft product contained within said sterilepackage, said tissue graft product comprising a submucosa-containing orrenal capsule-containing collagen layer, said collagen layer having aplurality of slits therein providing a mesh pattern.
 32. The medicalproduct of claim 31, wherein said mesh pattern is effective to providean expansion ratio of at least about 1.2:1 to said collagen layer in ahydrated condition.
 33. The medical product of claim 31, wherein saidcollagen layer comprises at least two submucosa layers, said submucosalayers bonded to one another.
 34. The medical product of claim 31,wherein said collagen layer comprises renal capsule.
 35. A tissue graftproduct useful for treatment of an exuding, open cutaneous wound,comprising a submucosa-containing or renal capsule-containing collagenlayer, said collagen layer having a plurality of slits therein, saidslits sufficient in number and spacing to allow drainage when applied tothe exuding open cutaneous wound so as to maintain contact betweentissue of the wound and the tissue graft product.